The present invention relates to optically active cephalosporin analogs and, more particularly, it pertains to optically active compounds of cephalosporin analogs represented by the general formula (I) ##STR1## wherein R.sub.1 represents a hydrogen or a lower alkyl group having 1 to 5 carbon atoms, R.sub.2 represents a hydrogen or a protective group of carboxylic acid selected from straight or branched alkyl groups having 1 to 5 carbon atoms, straight or branched lower alkoxymethyl groups having 1 to 5 carbon atoms, straight or branched halogenated alkyl groups having 1 to 5 carbon atoms, lower alkylsulfonylethyl groups, arylmethyl groups having 7 to 12 carbon atoms, substituted silyl groups, substituted arylmethyl groups having 7 to 20 carbon atoms and a group represented by the formula (VI) ##STR2## wherein R.sub.3 is a straight or branched lower alkyl group having 1 to 6 carbon atoms, a straight or branched lower alkoxy group having 1 to 6 carbon atoms or a phenyl group and R.sub.4 is a hydrogen or a straight or branched lower alkyl group having 1 to 6 carbon atoms, Q represents a hydrogen or a halo group selected from bromo, chloro, fluoro and iodo, A.sub.2 represents a hydrogen, a lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkinyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an aryl group, those groups being unsubstituted or substituted with suitable substituent(s) which are selected from carboxyl group, cyano group, a halo group, carbamoyl group and a lower alkyloxycarbonyl group having 1 to 4 carbon atoms, and the hydrogens at the 6- and 7-positions have cis configuration and pharmaceutically acceptable salts thereof.
Heretofore, a carbacephem compound, which is named according to the nomenclature in J. Am. Chem. Soc. 96, 7584 (1974), wherein the sulfur atom of cephalosporin is replaced with a CH.sub.2 and which has a substituted methyl group at the 3-position is described in the above reference and J. Med. Chem. 20, 551 (1977). However, no compound having especially strong antibacterial activity has been reported. In Japanese Published Unexamined Patent Application No. 9296/79 (German Offenlegungsschrift No. 2716707), a compound represented by the general formula (I) wherein R.sub.1, R.sub.2 and Q are a hydrogen and A.sub.2 is a methyl group is mentioned but neither practical embodiment for preparing the compound nor antibacterial activity thereof is described in the reference.
The present inventors have succeeded in preparing carbacephem compounds having various substituents at the 4-, 5- or 3-position, numbering system of which is as shown in formula (I). The compounds are described in the specifications of Japanese Published Unexamined Patent Application No. 128591/79, G.O. No. 2911786, Japanese Patent Application No. 162008/78 now Japanese Published Patent Application No. 87791/80 and U.S. patent application Ser. No. 23,645 filed on Mar. 23, 1979. "G.O." refers to German Offenlegungsschrift hereinafter.
Furthermore, the present inventors have succeeded in preparing novel acylated carbacephems which are new antibiotics having strong antibacterial activities. The compounds are described in the specification of Japanese Published Unexamined Patent Application No. 128591/79, G.O. No. 2911787, U.S. patent application Ser. No. 125,861, filed Feb. 29, 1980 and Japanese Published Patent Application No. 87791/80.
Among the compounds which were provided by the present inventors and represented by the general formula (II) ##STR3## (wherein X' is a conventional acyl group employed in the chemistry of cephalosporins and penicillins, R'.sub.1 represents a hydrogen atom, a lower alkyl group or a lower acyloxy group, and R'.sub.2 represents a hydrogen atom or an ester-protecting group conventionally employed in the field of the chemistry of penicillins and cephalosporins, that is, an alkyl group having 1 to 5 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, etc., a halogenated alkyl group having 1 to 5 carbon atoms such as chloromethyl group, 2,2,2-trichloroethyl group, 2,2,2-trifluoroethyl group, etc., an arylmethyl group having 7 to 20 carbon atoms such as benzyl group, diphenylmethyl group, triphenylmethyl group, etc., an arylmethyl group having 7 to 20 carbon atoms and having methoxy group, nitro group, etc. on the phenyl ring, a substituted silyl group such as trimethylsilyl group or triphenylsilyl group or a group enzymatically or nonenzymatically readily eliminable in vivo, for example, a group represented by the general formula ##STR4## wherein R.sub.4 represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, R.sub.3 represents a lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms or phenyl group, etc.), the acyl compound represented by the formula (I') ##STR5## (wherein R.sub.1, R.sub.2 and A.sub.2 have the same meanings as defined above, B represents an unsaturated six membered carbocycle which is selected from cyclohexenyl group, cyclohexadienyl group and phenyl group or a five or six membered heterocycle, A.sub.1 represents substituent(s) which is selected from hydrogen atom, hydroxyl group, a lower alkoxy group having 1 to 4 carbon atoms, a halo group, nitro group, amino group, aminomethyl group, methylsulfonamide group and a lower acyloxy group having 1 to 4 carbon atoms, and n is a number of 0 to 5) which has the carbacephem ring represented by the formula (III) (shown below) are reported to have strong antimicrobial activity against Gram-positive and Gram-negative microorganisms in Japanese Patent Application Nos. 122402/78, 133071/78, 162006/78, 162007/78, published respectively as Japanese Published Unexamined Patent Applications Nos. 49375/80, 59185/80, 87789/80 and 87790/80, (German Offenlegungsschrift No. 2911787), etc. Especially the acyl compounds having the carbacephem ring represented by the general formula (I") ##STR6## wherein A.sub.2 has the same significance as defined above, R".sub.1 represents a hydrogen or a methyl group and OA.sub.2 has syn configuration are reported to have strong antimicrobial activity against Gram-positive and Gram-negative microorganisms in the aforementioned patent applications. Hereinafter, compounds represented by the general formula (I), (II), (III), . . . are identified as Compound [I], Compound [II], Compound [III], . . . , respectively.
Since cephalosporin analogs mentioned above are prepared by totally synthetic methods using optically inactive starting materials and reagents, they are optically inactive unless they have a certain optically active acyl group such as D-phenylglycyl group described in the specification of Japanese Published Patent Application No. 87789/80 and U.S. patent application Ser. No. 125,861 (German Offenlegungsschrift No. 2911787).
Accordingly, there is a demand for optically active analogs and methods for production thereof. To this end, it has now been found that certain optically active carbacephem compounds can be prepared which have unexpectedly increased biological activity.